A new form of immunotherapy that targets not only glioblastoma cells but also the immune cells the tumour hijacks to protect itself has shown promising results in laboratory models, offering a potential breakthrough for the most aggressive and deadliest form of brain cancer. Researchers at King’s College London and McMaster University in Canada have engineered CAR-T cells to recognise a protein called GPNMB, which is found on the surface of both glioblastoma cells and the tumour-supporting macrophages that normally help defend the body against infection.
Glioblastoma, a grade 4 tumour that grows and spreads rapidly, has a median survival time of just 12 to 18 months. Around 3,200 people are diagnosed with the disease every year in the UK, and only about 4% of those diagnosed will survive for five years or more. In England, the five-year survival rate for all brain cancers stands at 12.9%, compared with an average of 56% across all cancers. Its invasive nature makes surgical removal difficult, and existing treatments have limited effectiveness.
The novel approach addresses what lead author Professor Sheila Singh, professor of neuro-oncology and neurosurgery at King’s College London and McMaster University, describes as a “connected tumour-immune ecosystem.” “Glioblastoma is not made up of cancer cells alone,” she said. “A large portion of the tumour consists of immune cells called macrophages. These cells normally help defend the body against infection, but glioblastoma can recruit and reprogramme them to help the tumour grow, suppress immune attacks, and resist treatment.”
By engineering CAR-T cells — a type of immunotherapy that retrains a patient’s own T cells to recognise and attack cancer — to target GPNMB, the team was able to strike on two fronts at once. “Instead of treating glioblastoma as only a mass of cancer cells, we need to think of it as a connected tumour-immune ecosystem,” Professor Singh added. “Our approach targets both the tumour and the environment that allows it to thrive. By going beyond the cancer cells alone, we are also targeting immune cells that help shield the tumour from treatment.”
GPNMB, a transmembrane glycoprotein, is overexpressed in glioblastomas and is associated with tumour progression and poor clinical outcomes. It promotes an immunosuppressive tumour microenvironment by increasing M2-polarization in macrophages and microglia, and reducing the activation and proliferation of T cells. Previous studies have shown that eliminating GPNMB in glioblastoma cell lines decreases proliferation and prolongs survival in mouse models, and that higher levels of GPNMB in patient biopsy samples correlate with increased survival risk, marking it as a potential prognostic indicator.
In the latest preclinical work, using glioblastoma models that replicate human biology — including those derived directly from patient tumours — the engineered CAR-T cells eliminated tumours and suggested the possibility of long-term disease-free survival. “Our work suggests we may also need to dismantle the immune support system that helps glioblastoma survive,” said study co-lead author Shan Grewal of McMaster University.
CAR-T therapy has already shown dramatic results in other cancers, particularly blood cancers such as leukaemia and lymphoma, and several CAR-T treatments are now routinely available on the NHS for specific conditions. However, translating that success to solid tumours like glioblastoma poses additional challenges, including limited T-cell trafficking into the tumour and the highly immunosuppressive tumour microenvironment. Researchers are also exploring “off-the-shelf” CAR-T cells made from healthy donors, which could be faster, stronger, and more affordable than patient-specific therapies. Another parallel line of investigation by Professor Singh’s group has identified uPAR as a promising target in recurrent glioblastoma, with uPAR-targeting CAR-T cells also showing success in laboratory and animal models by killing tumour cells and reducing tumour growth.
The work was published in the journal Nature, with related findings in Science Translational Medicine and Nature Medicine. Despite the encouraging preclinical results, the research remains at an early stage, and further studies are needed before clinical trials can begin. A Phase I trial known as CARGO is already under way in the UK, investigating CAR-T cells that target a different protein, EGFRvIII, in patients with relapsed or recurrent glioblastoma.
Call for investment and NHS readiness
Dr Karen Noble, director of research and policy at Brain Tumour Research, highlighted the urgency of turning laboratory breakthroughs into accessible treatments. “New treatment options that can tackle the complexity of this deadly cancer are vital. These results are really promising – particularly as CAR-T has been used successfully in other cancer areas and so hopefully this innovation can be translated rapidly for patients,” she said. “Importantly, breakthroughs in the laboratory will only change the story for the brain tumour community once they are turned into treatments in clinics across the UK and research like this highlights the need for more investment to enable discoveries and accelerate the path to patients. That’s why we are calling on government to build a more attractive financial and regulatory environment in the UK for the life science industry, to ensure that more clinical trials can get under way and more patients can access these.”
Yasmin Sheikh, head of policy and public affairs at Anthony Nolan, stressed the transformative potential of CAR-T therapy and the infrastructure needed to deliver it. “At Anthony Nolan, we’ve seen first-hand how transformative CAR T-cell therapy can be for people with blood cancer. This research is an exciting step forward and adds to growing evidence that CAR T-cell therapy could also offer new hope for people living with other forms of cancer, including brain cancer,” she said. “While these findings are highly encouraging for the future, we also need to be thinking about how innovative treatments like this one can be delivered in practice. The NHS must ensure that it has the workforce and infrastructure in place so that patients can benefit from new therapies without delay.”